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These conditions can arise from diverse causes including trauma and injury, tumor resection, congenital abnormalities, and age-related degeneration. In the past decades, administration of chemically modified mRNA (cmRNA) encoding growth factors and transcriptional regulators has demonstrated effectiveness in repairing musculoskeletal tissues in preclinical studies. This review summarizes recent advancements in bone, tendon, cartilage, intervertebral disc, and muscle regeneration achieved through the localized delivery of protein-encoding mRNAs to express therapeutic target proteins. Delivery of cmRNA encoding growth factors such as BMP-2, BMP-9, VEGF, FGF-18, and IGF-1, or transcriptional regulators including Runx1, to various animal models has shown beneficial effects on bone, tendon, cartilage, and muscle injury repair in preclinical models. Alongside these progresses, the advantages and disadvantages of applying chemically modified mRNA for musculoskeletal tissue regeneration are also discussed. While studies show the promise of cmRNA for therapeutic applications in orthopedic tissue regeneration, more research is required to optimize growth factors and delivery methods, as well as validate long-term safety and efficacy prior to successful translation into new therapies to benefit patients.<\/jats:p>","DOI":"10.3390\/jfb17040167","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T08:08:34Z","timestamp":1775030914000},"page":"167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protein-Encoding Chemically Modified mRNAs for Musculoskeletal Tissue Regeneration and Repair"],"prefix":"10.3390","volume":"17","author":[{"given":"Britney S.","family":"Force","sequence":"first","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5833-1548","authenticated-orcid":false,"given":"Xueqin","family":"Gao","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johnny","family":"Huard","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Palazzo, C., Ravaud, J.F., Papelard, A., Ravaud, P., and Poiraudeau, S. 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